Hyperalgesia- a pain response initiated by a normally non-painful stimulus is present in conditions ranging from pancreatic cancer to diabetic neuropathies. Management of pain represents a major hurdle faced by the clinician during quality of life in these patients. I appreciate that current therapies are good, but inadequate. My perspective is that advances in therapies will benefit from greater understanding of the molecular basis of nociceptive signaling, particularly between neurons and glia. The contribution of spinal non-neuronal cells to the integration of nociceptive processing broadly defines my overall research emphasis. More specifically, my interests have focused on the role of metalloproteinases in spinally mediated nociception. Importantly, this overall topic is a focus of the neuronal environmental group at NINDS and is in accord with the NINDS call for research on "Mechanisms, Models, Measurement and Management in Pain Research" through a broadening of the definition of molecular inducers and mediators of nociception, with the aim of yielding new areas of therapeutic potential. My proposal aims to achieve these goals by utilizing immunohistochemistry, Western blotting, ELISA, and zymograms of spinal cord and cerebral spinal fluid samples to determine a time course and cellular localization of matrix metalloproteinase 3 (MMP-3), and associated regulatory proteins such as tissue inhibitor of metalloproteinase 1 (TIMP-1), and osteopontin in a model of inflammatory pain. The next step will be to define through spinal delivery of small molecule inhibitors and anti-sense mRNA the requirement for MMP-3 and osteopontin in onset of inflammatory nociceptive behavior. This behavior will be assessed in established behavioral models, the von Frey tactile and modified Hargreaves box tests for tactile and thermal responses. Mechanistically, these aims will identify the necessity and sufficiency for MMP-3 and osteopontin. As a result, the final step will be to identify the effects of spinal MMP-3 on pain behavior and determine the role of known MMP-3 substrates such as MMP-2, MMP-9, brain derived neurotrophic factor (BDNF) and proteinase activated receptors in MMP-3 mediated pain behaviors. Further investigations will investigate the requirement for microglia in this effect by mechanistic interventions, such as with spinal delivery of minocycline. PUBLIC HEALTH RELEVANCE These studies will expand our understanding of the basic biology of pain processing, and point to potential therapeutic targets. Many chronic pain conditions are inadequately alleviated by available medications. This proposal will examine the role of matrix metalloproteinases in the onset and the duration of pain sensations.